St. Jude method democratizes access to T-cell receptor analysis

Studying T cells, the immune cells most responsible for responding to infections and cancers, just received a significant boost in the form of a new technique from St. Jude Children’s Research Hospital. While T-cell analysis can reveal much about how the immune system works, it can be prohibitively expensive and logistically impractical. This is due to the necessity of analyzing millions of T cells while accurately detecting the pairings of the two halves of their most critical protein, the T-cell receptor. A St. Jude initiative has overcome these limitations by creating a method that provides the most complete picture of a person’s entire T-cell repertoire to date, at 10% of the cost of pre-existing approaches. The technique and its initial findings were published today in Nature Methods.

The new technique, Throughput-Intensive Rapid TCR Library sequencing (TIRTL-seq), performed far better than existing methods. In the study, the researchers showed they could accurately process up to 30 million T cells at one time, greatly expanding on the maximum limit of 20 thousand cells for the most common current techniques. Additionally, while the conventional approach costs about $2,000 to process 20 thousand cells and requires scientists to run the method multiple times, TIRTL costs $200 for 10 million cells, which scientists could analyze in a single run.

“We have democratized access to understanding immune memory,” said Victor Torres, PhD, St. Jude Department of Host-Microbe Interactions chair, who oversees TIRTL-seq as part of a departmental Shared Resource. “TIRTL-seq can perform a highly detailed analysis of many T-cell receptors at a cost that makes these experiments feasible for more scientists than ever before, which we hope will push T-cell science forward.”

St. Jude targeted T-cell receptor sequencing with TIRTL

T cells use T-cell receptors to find threats and carry out their duties as immune cells. Therefore, understanding the differences between all T-cell receptors present in an individual (called their T-cell repertoire) could explain differences in immune responses. In 2023, St. Jude launched TIRTL to find a way to bring costs down and improve the volume of T cells that could be processed to ultimately decode the T-cell repertoire and apply these insights to catastrophic childhood diseases.

The resulting method, TIRTL-seq, uses a mix of physical automation, streamlined computational processing and improved laboratory methods to limit costs. Splitting full samples into many subsamples enables statistical methods that result in better sequencing and pairing results, allowing more cells to be processed. When combined, these methods created a powerful new technique that outperformed benchmarks from all competing technologies.